tbuckley/cabot-search huggingface dataset:
Abstract 6404: Clinical scenario of immune checkpoint inhibitor treatment in metastatic nasopharyngeal carcinoma
Authors: Cheng-Lung Hsu, Yung-Chia Kuo
Journal: Cancer Research (2023)

Abstract Advanced in local treatment technology and early detection methodology, distant metastasis became a critical issue in Nasopharyngeal carcinoma (NPC). Recently, cancer immunotherapy especially immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) and PD-1 ligand (PD-L1) monoclonal antibodies (Mabs) had a rapid progress in cancer patient management. We try to clarify the clinical scenario of immune-related parameters in metastatic NPC. We had check 81 metastatic tissue PD-L1 expression without ICI treatment from the tissue bank of CGMH, Linkou, during 2005~2019. Using anti-PD-L1 antibody, 22C3 Dako, tumor proportional score (TPS) was positive in 43.2% (35/81) checked tissue and combine positive score (CPS) was positive in 58.0% (47/81) tissue respectively. For overall survival (OS) combined with PD-L1 expression in metastatic tissue analysis, positive CPS but not TPS correlated with longer survival with statistical significance (TPS: &amp;gt;0% vs =0%, median survival, 24m vs 22.5m, p=0.615186; CPS: &amp;gt;0% vs =0%, median survival, 28m vs 16m, p=0.003709). Retrospectively analysis of metastatic NPC treatment of combination of chemotherapy, ICIs, and local treatment in our institute in the past 6 years, total 40 patients was enrolled with median overall survival of 34.1 months. Objective response rate by RECIST criteria for immunotherapy-based regimen was 75% (CR:40%; PR:35%) and disease control rate was 85%. According to response by RECIST criteria, median overall survival were 34.1 months vs. 16.7 months respectively for responders and non-responders. With pre-treated NLR as cutoff value of 1.6, difference of median overall survival between two groups (responder vs nonresponder) was statistically significant (p=0.021). We also found that lower median post-treatment NLR in responders than in non-responders (1.4 vs. 3.2, p=0.013). Using rapid lymphocyte amplification protocol via IL-2 stimulation, the PBMC from most of the patient received ICIs treatment can be amplified 1~10 folds and positively correlated with total lymphocyte count. Through flowcytometry analysis, we found these amplified PBMC was lymphocyte dominant and rich in CD8+. We also found these amplified PBMC can kill the NPC EBV-positive cell line and xenograft in vitro and in vivo. These results demonstrated that combination of chemotherapy, ICIs, and local treatment will benefit metastatic NPC patients. Citation Format: Cheng-Lung Hsu, Yung-Chia Kuo. Clinical scenario of immune checkpoint inhibitor treatment in metastatic nasopharyngeal carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6404.
Abstract 2226: Modeling the role of Tet-deficiency and restoration in Bcl2-driven B cell lymphoma progression
Authors: Minh Quang Lam, Luisa Cimmino
Journal: Cancer Research (2023)

Abstract Loss of function in DNA methylation regulators such as the Ten-eleven translocation (TET1-3) proteins, have been implicated in the progression of lymphoma. TET enzymes constitute a family of iron and αKG-dependent dioxygenases that oxidize 5-methylcytosine in DNA to promote demethylation and the reversal of gene silencing. The TET enzymes require vitamin C for their optimal catalytic activity, however, many patients with hematological malignancies are vitamin C deficient. Enhancing and restoring TET function with high-dose vitamin C has been shown to block the progression of solid tumors and blood malignancies. A combination of genetic and epigenetic diversity in lymphoma can result in the aberrant overexpression of oncogenes, loss of tumor suppressor function, and genomic instability. Our research models Bcl2-driven B cell lymphoma with Tet-deficiency using transgenic RNAi for the knockdown of Tet1 or Tet2. In vitro, our results have shown that this model shows increased self-renewal capacity of early B cell progenitors and precursors that can be suppressed by genetic restoration of Tet expression or upon treatment with vitamin C. In vivo, the B cell compartment of mice with Bcl2 overexpression and Tet1 or Tet2 deficiency exhibit a block in B cell maturation during a long period of pre-malignancy, and a decreased frequency of follicular B cells in the spleen from 3 months of age. Our aim is to determine mechanistically the effects of Tet-deficiency on B cell lymphoma progression and whether vitamin C can restore Tet activity to suppress lymphoma progression. Citation Format: Minh Quang Lam, Luisa Cimmino. Modeling the role of Tet-deficiency and restoration in Bcl2-driven B cell lymphoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2226.
Abstract 2605: LOXL3 knock out affects pathways which involve cytoskeleton regulation, proliferation and apoptosis in glioblastoma cells
Authors: Talita S. Laurentino, Roseli S. Soares, Antonio M. Lerario, Suely K. Marie, Sueli Mieko Oba-Shinjo
Journal: Cancer Research (2023)

Abstract Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family of copper-dependent amino oxidase, is responsible for the crosslinking of collagen and elastin. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among the tumors with the highest LOXL3 expression levels. Moreover, LOXL3 expression increased with malignancy grade amongst diffusely infiltrative astrocytomas (from grade 2 to 4). In the present work, CRISPR-Cas9 gene editing was used to knock out LOXL3 in the human glioma U87MG cell line to evaluate the role of LOXL3 in glioblastoma. Analyses of protein expression level and genomic mutation mediated by CRISPR-Cas9 by two different sgRNA (denominated sgRNA1 and 2) were performed and the knock out efficiency and genome editing were confirmed. Transcriptome analysis of these cells revealed a downregulation of genes that coded for proteins involved in microtubule organization, cell division, and vesicle trafficking. On the other hand, upregulated genes when LOXL3 was knocked out in U87MG cells were involved in actin cytoskeleton, negative regulation of gene transcription, including chromatin remodeling, and cell-cell adhesion. Functional in vitro assays showed that LOXL3 knocked out cells presented decreased cell proliferation due to longer cell cycles with increased G1 and G2/M checkpoints compared to control cells. Additionally, LOXL3 knocked out U87MG cells presented a higher percentage of cells in the early phase of apoptosis with an increment after temozolomide treatment. Our results suggest an important role of LOXL3 in glioblastoma possibly mediated by cytoskeleton regulation, affecting cell proliferation, cell cycle, and cell death. These results reinforced the importance of LOXL3 in tumors, especially in glioblastoma, highlighting it as a potential therapeutic target. Citation Format: Talita S. Laurentino, Roseli S. Soares, Antonio M. Lerario, Suely K. Marie, Sueli Mieko Oba-Shinjo. LOXL3 knock out affects pathways which involve cytoskeleton regulation, proliferation and apoptosis in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2605.
Abstract 5653: LCB97, an antibody drug conjugate (ADC) targeting a novel tumor antigen for the treatment of multiple solid tumors
Authors: Yeojin Jeong, Gunther Spohn, Flavio Mehli, Chul-Woong Chung, Changsik Park
Journal: Cancer Research (2023)

Abstract LCB97 is an antibody-drug conjugate (ADC) directed against a novel tumor antigen, composed of monomethyl auristatin E (MMAE) as payload (DAR 4) and the humanized IgG1 antibody AFF4 generated by Elthera. AFF4 targets a novel antigen preferentially expressed in various solid tumors including pancreatic cancer, ovarian cancer, colon cancer, breast cancer and melanoma. LCB97 generated by using LCB’s ConjuAllTM technology with AFF4 showed potent cytotoxicity in various cancer cell lines including breast cancer (BC), ovarian cancer (OC), pancreatic cancer (PaC), small cell lung cancer (SCLC), colorectal cancer (CRC) and melanoma. LCB97 also showed excellent anticancer efficacy in several cell line-derived xenograft (CDX) models, including BC, CRC, OC and melanoma. Preliminary toxicity assessment in cynomolgus monkeys (an AFF4 cross reactive species) demonstrated that LCB97 was well tolerated within the estimated therapeutic index of ~20 for repeat dosing. In conclusion, LCB97, generated by combining theAFF4 monoclonal antibody of Elthera and the highly innovative ConjuAllTM platform technology of LegoChem Biosciences is a promising next-generation ADC for the treatment of various solid cancers, including BC, CRC, melanoma, OC and PaC. Citation Format: Yeojin Jeong, Gunther Spohn, Flavio Mehli, Chul-Woong Chung, Changsik Park. LCB97, an antibody drug conjugate (ADC) targeting a novel tumor antigen for the treatment of multiple solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5653.
Abstract 670: Sex differences in the innate immune response to lung cancer
Authors: Lauren A. May, Joseph W. Landry, Rebecca Martin, Howard Y. Li, Jennifer Koblinski, Paula D. Bos
Journal: Cancer Research (2023)

Abstract Lung cancer is the second most diagnosed cancer. Lung cancer exhibits a sex difference, though the exact mechanisms behind this difference are not well understood. Men have a higher lifetime risk of developing lung cancer and often have more severe disease than women. There are thought to be multiple factors that contribute to this difference, including the environment, lifestyle, sex hormones, and differing immune responses. Mouse tumor models of lung, breast, colon, melanoma and kidney were used in immune competent or immune compromised mouse models treated with the chemotherapy ABT-263. The study of the immune response to lung tumors utilized ex vivo killing assays, multicolor flow cytometry, and clonogenic survival, as well as humanized mice and patient-derived xenografts. We observe a sex difference in two models of lung cancer in immunocompetent mice, but not in models of breast, colon, kidney, or melanoma. This difference is dependent on the innate immune system, specifically through natural killer cells and macrophages. This sex difference is lost in ovariectomized mice. Multicolor flow cytometry shows differences in innate immune cell populations in tumors and spleens in males and females. Preliminary data suggests the pro-apoptotic ligand TRAIL secreted from innate immune cells is more effective on cells exposed to female compared to ovariectomized female mouse serum. Reduced tumor growth in female mice can be further enhanced with ABT-263, and this effect requires NK cells. Patient-derived xenografts transplanted into female humanized mice grow more slowly than those transplanted into non-humanized mice, confirming the role of the immune system in modulating tumor growth. This research opens the potential for immune stimulating therapies, combined with ABT-263, as a novel treatment approach. Citation Format: Lauren A. May, Joseph W. Landry, Rebecca Martin, Howard Y. Li, Jennifer Koblinski, Paula D. Bos. Sex differences in the innate immune response to lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 670.
Abstract 2604: Functional analysis of p53 codon 72 polymorphism with cysteine substitution in cancer cells
Authors: Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract The p53 codon p72 polymorphism with proline (p53P72)/arginine (p53R72) substitution is associated with cancer incidence. Cysteine(C) substitution at p53 codon 72 polymorphism (p53C72) is rarely studied in cancer patients. A patient who developed AML and who carries p53C72 was described (El-Deiry, 2022 WIN Symposium). The patient’s family has high rates of cancer susceptibility in the women some of whom carry FANCC alterations and other alleles. To examine the functional characteristics of different p53 alterations at codon 72, we generated plasmids expressing p53C72, p53 R72 or p53P72. The variants of p53 were overexpressed in p53-null cancer cells by transient transfection of the plasmids. We tested functions of the p53 codon 72 polymorphisms (p53C72, p53R72 and p53P72) in two cancer cell lines (Soas-2 and HCT116 p53 null) with different expression levels of the p53 variants at different time points. To examine the effect of codon 73 variants on p53 transactivation, we performed a PG13-Luciferase reporter assay and examined the endogenous p53 targets at the protein level. The luciferase-reporter assay showed that all the three variants of the p53 codon p72 variants increased PG-13 luciferase expression at early time points. The Western blot assay showed that the p53C72, the p53R73 and the p53P72 increased endogenous p21, DR5, puma and MDM2 at the protein levels at different time points. The p53C72 increased the p53 targets and PG13-driven luciferase expression much higher than the p53R72 and the p53P72. These results suggest that the p53 codon 72 variants (C72, R72 and P72) retain wild-type activity for p53-mediated transcription, and p53C72 has the highest potency among them. We examined the effect of the p53 variants on cell growth and death. PARP cleavage (a marker of cell apoptosis) was induced in cells overexpressing all the three p53 codon 72 variants. We observed a lesser potency of p53C72 to induce PARP cleavage compared to p53R72 and p53P72. Colony formation assay showed a suppressive effect of p53C72, p53R72 and p53P72 on cancer cell growth. Our studies demonstrate some differences of in wild-type functions of p53 p53C72, p53R72 and p53P72 alleles. Citation Format: Shengliang Zhang, Wafik S. El-Deiry. Functional analysis of p53 codon 72 polymorphism with cysteine substitution in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2604.
Abstract 2589: <i>TROP2</i> gene copy number variations are a hallmark of glioblastoma and MEN-2A cancers
Authors: Saverio Alberti, Marco Trerotola, Antonino Moschella, Emanuela Guerra
Journal: Cancer Research (2023)

Abstract TROP2 mutations are not required to trigger activation of tumor growth and metastasis. However, expression of Trop-2 is affected by DNA methylation in choriocarcinomas, i.e. trophoblast-derived malignancies, and in lung adenocarcinomas, suggesting that loss of TROP2 expression may provide a selective advantage in specific tumor types. Intriguingly, amplification of the TROP1/EPCAM and TROP2/TACSTD2 genes was found to be driven by alterations of DNA methylation, with parallel LOH in sister cell clones. Consistent, mutations of TP53 were shown to induce amplification of TROP genes through loss of DNA methylation. Hence, we investigated whether LOH/DNA methylation of the TROP2 gene and gene amplification are selectively associated with specific tumor types. Our findings indicate that TROP2 amplification occurs in a subgroup of aggressive glioblastomas (15.7%, n=3/19), suggesting impact on malignant progression. On the other hand, TROP2 LOH was shown to occur in the majority of low-grade gliomas (80%, n=4/5). Investigation on the TROP2 gene in MEN-2A revealed that LOH of TROP2 was somatically acquired in 25% of phaechromocytomas and medullary thyroid carcinomas (n=6/24), but did not appear as a heritable trait in the germline. TROP2 gene copy number variations were rarely detected in other cancer types, suggesting tumor subtype-specific impact. Citation Format: Saverio Alberti, Marco Trerotola, Antonino Moschella, Emanuela Guerra. TROP2 gene copy number variations are a hallmark of glioblastoma and MEN-2A cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2589.
Abstract 345: Cutaneous T-cell lymphoma: ectopic expression of gametocyte specific factor 1 (GTSF1) stimulates the Th phenotype
Authors: Amelia Martínez Villarreal, Ivan Litvinov
Journal: Cancer Research (2023)

Abstract Diagnosis of Cutaneous T-Cell Lymphomas (CTCL) can take up to 6 years, increasing the risk of disease progression in these patients. Transcriptomic analyses have helped identify several diagnosis biomarkers, such as TOX, KIRD3DL2, GTSF1 and others. Although not officially a Cancer-Testis (CT) antigen, ectopic expression of Gametocyte Specific Factor 1 (GTSF1), presents the same advantages than CT antigens. Its germline-cell restricted expression potentially makes this gene easily identifiable by the immune system and a therapeutic target with less side effects. The role of GTSF1 has been elucidated in mice, where it controls retrotransposon expression during germ-cell development. Here, we investigate the molecular function of GTSF1 in CTCL. Using shRNA-mediated GTSF1 knockdown in CTCL cell lines, our current work demonstrates an unexpected role of GTSF1 regulating the Th phenotype of CTCL cells. With multiple approaches (qRT-PCR, Western blotting and a dual-luciferase based retrotransposition assay) we concluded that GTSF1 knockdown does not lead to retrotransposon reactivation. Transcriptome analysis with RNA-Seq, followed by differential gene expression analysis with DESeq2 and pathway enrichment analysis with GO, KEGG, Reactome and WikiPathways, suggested an involvement of GTSF1 in the Th phenotype of CTCL cells. Differential gene expression analysis revealed 12,496 differentially expressed genes (p adjusted &amp;lt; 0.05). Pathway enrichment analysis demonstrated an enrichment of several pathways including response to stimulus, immune response, response to cytokine and inflammatory response. More specifically, GTSF1 knockdown leads to an upregulation of the key cytokines associated with a Th1 phenotype, IFNG and TNF. Disease progression of CTCL is associated with a decrease in Th1 cytokine production and an enhanced Th2 cytokine production by malignant T cells. These findings shed light on the molecular function of GTSF1 as a regulator of the Th phenotype in CTCL and paves the way for the development of a valuable treatment target for CTCL patients. Citation Format: Amelia Martínez Villarreal, Ivan Litvinov. Cutaneous T-cell lymphoma: ectopic expression of gametocyte specific factor 1 (GTSF1) stimulates the Th phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 345.
Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology
Authors: Jaffer A. Ajani, Thomas A. D’Amico, David J. Bentrem, David Cooke, Carlos Corvera, Prajnan Das, Peter C. Enzinger, Thomas Enzler, Farhood Farjah, Hans Gerdes, Michael Gibson, Patrick Grierson, Wayne L. Hofstetter, David H. Ilson, Shadia Jalal, Rajesh N. Keswani, Sunnie Kim, Lawrence R. Kleinberg, Samuel Klempner, Jill Lacy, Frank Licciardi, Quan P. Ly, Kristina A. Matkowskyj, Michael McNamara, Aaron Miller, Sarbajit Mukherjee, Mary F. Mulcahy, Darryl Outlaw, Kyle A. Perry, Jose Pimiento, George A. Poultsides, Scott Reznik, Robert E. Roses, Vivian E. Strong, Stacey Su, Hanlin L. Wang, Georgia Wiesner, Christopher G. Willett, Danny Yakoub, Harry Yoon, Nicole R. McMillian, Lenora A. Pluchino
Journal: Journal of the National Comprehensive Cancer Network (2023)

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.